Virpax_Headers_Science-2BEHIND THESCIENCE

THE DATA BEHIND OUR PRODUCTS

Jeffrey Gudin, M.D., Virpax’s Chief Medical Officer, has presented various posters on Virpax’s scientific advancements and discoveries.

A poster entitled Enkephalin as a Potential Analgesic and CNS Modulator appeared at PAINWeek 2021. It shows that nanoparticle encapsulation of enkephalin would lead to effective brain delivery and analgesia.

Two other posters were presented at the 2019 Military Health System Research Symposium (MHSRS) on August 21, 2019:

The first poster, NSAID Topical Diclofenac Epolamine Spray Film Epoladerm for the Management of Acute Musculoskeletal Pain explains how the Virpax proprietary 12-hour topical metered-dose spray film formulation is being studied to manage acute musculoskeletal pain.

The second poster, Sustained Non-Opioid Pain Management in Prolonged Field Care and Hospital Settings Using Probudur describes how the company’s proprietary liposomal bupivacaine gel demonstrated the ability to provide post-operative pain control for up to 96 hours.

new pain management solutions

ENVELTA™

Enkephalin as a Potential Analgesic and CNS Modulator

INTRODUCTION

  • Endogenous peptides with analgesic potential include endorphins via binding to the mu receptor, dynorphins via the kappa receptor and enkephalins via the delta receptor
  • Kappa and delta opioid agonists have been shown to provide analgesic benefit while sparing mu agonist toxicity1
  • Preclinical data supports analgesia from enkephalin without significant opioid tolerance or drug liking
  • Typically, exogenous enkephalins are rapidly degraded and have difficulty accessing the CNS2
  • Using a novel encapsulation method known as Molecular Envelope Technology (MET), leucine-enkephalin, or L-ENK can be delivered via an intranasal formulation of “protected” nanoparticles. MET increases dwell time in the nares promoting delivery via the olfactory route across the blood brain barrier and into the central nervous system

MET increases dwell time in the nares promoting delivery via the olfactory route across the blood brain barrier and into the central nervous system

PRECLINICAL DATA

  • When studied in rats, polymer nanoparticles were able to transport MET encapsulated L-ENK to the brain via the intranasal route
  • Animals dosed with encapsulated     L-ENK nanoparticles showed a strong anti-nociceptive response in multiple assays of evoked pain, including hot plate, Freund’s adjuvant (CFA), and spinal nerve ligation
  • No analgesic tolerance was noted
  • Animals dosed intranasally with unencapsulated LENK did not show an analgesic response. L-ENK was effective in morphine tolerant animals
  • Conditioned place preference, a preclinical behavioral model used to study the rewarding and aversive effects of drugs, was not observed

POTENTIAL DELIVERY DEVICE

  • Neurons are exposed within the olfactory area of the nares4, facilitating the transport of drug compounds directly into the brain
  • For nose-to-brain delivery, the dose must be deposited in the olfactory region, and thus, a specialized delivery device is required
  • A propellant activated device has been identified that will be studied to deliver encapsulated enkephalin

SUPPORT

  • The National Institutes of Health (NIH) HEAL (Helping to End Addiction Long-term) Initiative is a government sponsored effort to speed scientific solutions to stem the national opioid public health crisis5
  • Under the NIH HEAL Initiative, Virpax Pharmaceuticals entered a collaborative research and development agreement through the National Center for Advancing Translational Sciences (NCATS) of the NIH to study the pharmacology and safety of an intranasal enkephalin formulation for the treatment of pain

CONCLUSION

  • An estimated 50 million (20%) of U.S. adults had chronic pain, with 20 million (8%) having high-impact chronic pain6—a debilitating medical condition that is complex and lacks effective treatments. The development of new therapies as viable alternatives to mu-opioids is urgently needed
  • Drug overdose deaths in the United States rose nearly 30% in 2020 to more than 93,000, with almost 70,000 involving opioids, according to preliminary data released today by the Centers for Disease Control and Prevention7.
    These data do not reflect a significantly greater number of non-fatal overdoses
  • Enkephalins are endogenous peptides reported to have a number of central and peripheral physiological effects. We tested the hypothesis that the nanoparticle encapsulation of enkephalin would lead to effective brain delivery and analgesia. The formulation studied above appears to protect enkephalin from rapid degradation on its nasally administered course through the olfactory neurons into the CNS

MET/L-ENK appeared effective in animal models of analgesia without obvious tolerance, and failed to show evidence of drug liking. Should studies advance in humans and translate to similar findings of safety and efficacy, this formulation has the potential to be a safe and effective analgesic of the future.

SUMMARY

Our data shows enhanced enkephalin transport to the brain using a novel Molecular Envelope Technology (MET), yielding analgesic effects in multiple preclinical models.

If data confirms analgesic benefit without respiratory depression or addiction, this enkephalin formulation may represent a potential broad-spectrum molecule to treat multiple types of acute and chronic pain and other CNS disorders.

  1. Cabot PJ, Carter L, Schäfer M, Stein C. Methionine-enkephalin-and Dynorphin A-release from immune cells and control of inflammatory pain. Pain. 2001 Sep;93(3):207-212. doi: 10.1016/S0304-3959(01)00322-0. PMID: 11514079
  2. Lalatsa, A.; Schatzlein, A.G.; Uchegbu, I.F. Strategies to deliver peptide drugs to the brain. Mol Pharm 2014, 11, 1081-1093, (doi:10.1021/mp400680d)
  3. Godfrey L, et al. Nanoparticulate peptide delivery exclusively to the brain produces tolerance free analgesia. Jrnl of Controlled Release Vol 270, 28 Jan 2018, p135-144
  4. The olfactory epithelium and olfactory receptor neurons, in Neuroscience, 3rd ed (Purves D, Augustine GJ, et al.) pp 342–353, Sinauer Associates, Sunderland, MA. (2004)
  5. https://heal.nih.gov
  6. https://www.cdc.gov/mmwr/volumes/67/wr/mm6736a2.html
  7. https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.html

EPOLADERM™

Topical NSAID Spray Film, A Novel Analgesic Formulation

Sustained Non-Opioid Pain Management

 

  • FDA is encouraging the development of new treatment options for patients in pain, especially treatments that are not addictive1. Current analgesics are wrought with adverse effects, such as abuse, hepatic, renal, GI and CV issues
  • Topical analgesics offer the potential to match the analgesic relief provided by oral agents but with minimal systemic adverse effects
  • Diclofenac gels, liquids and patches have demonstrated relief for both acute and chronic pain conditions
  • There is strong evidence in the literature for the use of topical diclofenac in the treatment of acute soft tissue injuries or chronic joint-related conditions, such as osteoarthritis
  • Poor adhesion, messy application, inconsistent dosing, and prolonged drying time makes available formulations less than optimal
  • Epoladerm is a first-in-class topical delivery system based on a proprietary spray film formulation
  • Metered dose spray (does not require tape reinforcement)
  • Active drug: Diclofenac epolamine (DHEP, diclofenac-N-(2- hydroxyethyl) pyrrolidine)
  • Spray film dries to a pliable, invisible depot in the skin and allows for application to joints and contoured areas
  • Novel formulation controls: Plume, Pressure, Dose, Delivery, Tackiness and other characteristics
  • Better performance (adhesion, accessibility and visual appeal) and lower cost compared to topical patch
  • Faster drying and less messy compared to topical gels/ointments
  • Potential for minimizing systemic adverse effects (AE’s) versus oral NSAIDs and lowering opioid usage
  • 505(b)(2) abbreviated FDA regulatory development pathway
  • Planned Clinical Trials: Comparator product Flector® topical diclofenac patch

NOVEL SPRAY FILM FORMULATION

Virpax novel spray film formulation

MULTIPLE DICLOFENAC FORMULATIONS TESTED TO IDENIFY EPOLADERM

Mean cumulative amount of drug permeated through human skin between 12 and 24 hours

EPOLADERM vs FLECTOR IN VITRO PERMEATION TESTING

Comparable or superior performance to diclofenac patch (data on file)

  • For nonopioid chronic pain treatments, consider topicals as alternative first-line; thought to be safer than systemic medications. Lidocaine for neuropathic pain and topical NSAIDs for localized osteoarthritis.4
  • Gels and liquids are associated with messy application, inconsistent dosing with a prolonged drying time
  • When a topical patch loses its adherence during wear, the amount of drug delivered to the patient may be reduced
  • Poor adhesion of patches is the #1 reported patch AE reported to FDA Adverse Event Reporting System (FAERS)3
  • Epoladerm adheres to curved, movable joint surfaces and those with movement
  • Should be less effected by changes in environmental temperature, humidity and contact with clothing or bedding

CONCLUSION

  • Topical NSAIDs provide pain relief in acute conditions such as sprains, strains and overuse injuries, potentially comparable to that provided by oral NSAIDs2
  • Epoladerm is an investigational topical NSAID Spray Film for the relief of pain
  • This is the first in class topical delivery system with reliable, consistent application without
    patch adhesion concern
  • Allows consistent topical administration via metered dosing
  • Expected to demonstrate comparable or improved efficacy compared to the diclofenac patch with an abbreviated regulatory path to FDA approval
  • Potential to improve compliance
  • Very low COGS enables pricing flexibility and improved payer access over competing brand and generic patches
  • Pending FDA submission via the
    505(b)(2) pathway

ADHESION

  • Adheres to skin surface
  • Dries in 1 minute

SPRAY FILM

  • Apply to joints on curved/contoured surfaces
  • Metered-dose
  • Applies invisibly
  • Small and easy to carry

HEALTH ECONOMIC OUTCOME BENEFITS

  • Potential for cost savings, improved medical outcomes, and improved patient satisfaction
  1. FDA S Gottlieb July 13, 2017 press release
  2. Cochrane review
  3. https://www.cdc.gov/drugoverdose/pdf/nonopioid_treatments-a.pdf Francio VT, Davani S, et al. Journal of Pain & Palliative Care Pharmacotherapy, 2017. 31:2, 113-120
  4. FDA Perspectives on Product Quality of Transdermal Drug Delivery Systems, Krishnaiah, October 2015

PROBUDUR™

Ultra-Long-Acting Local Anesthetics: Liposomal Encapsulated Bupivacaine

Sustained Non-Opioid Pain Management in Prolonged Field Care and Hospital Settings

  • Local anesthetics prevent the transmission of painful nerve impulses and are an integral component of postoperative pain management
  • Most available local anesthetics have a short duration of action necessitating opioid and other analgesic administration following surgery
  • Local anesthetics are relatively small molecules (<400D) and therefore are rapidly redistributed from their site of administration- limiting their duration of action
  • The risk of systemic toxicity from local anesthetics limits the dose that can be safely administered
  • There is a compelling need for an ultra-long-acting local anesthetic that would provide prolonged pain relief with a single administration

The co-developer of Doxil and a world-leading liposome researcher

  • Encapsulation of the local anesthetic bupivacaine into large multivesicular vesicles (LMVV or Bupisome) has been shown to be an effective means of prolonging analgesia
  • Probudur is an ultra-long-acting 3% bupivacaine liposomal gel under development for the management of postoperative pain
  • The prolonged retention of the LMVV at the site of administration extends the duration of action up to 96 hours
  • The slow release of the drug from the liposomal depot reduces the peak plasma levels, and therefore, the toxicity or trauma
  • This allows potential administration of higher bupivacaine doses for the management of pain after surgery

PROBUDUR CRYOGENIC TRANSMISSION ELECTRON MICROSCOPY (CRYO-TEM)

Cyro-TEM 1-2

Large Bupisome  (LMVV)

Studied in rabbits, rats, dogs, pigs – as well as human pharmacokinetic (PK) data

LMVVs are large structures which have a high level of encapsulated drug (trapped volume 21x higher than SUVs). Part of the bupivacaine is incorporated in the liposomal membrane which releases the drug slowly over time producing long-lasting analgesia.

Cyro-TEM 3-4

Small Unilamellar Vesicles loaded with Bupivacaine (LMVV)

EFFICACY/SAFETY DATA OBSERVATIONS2

  • Pig postoperative pain – superior to bupivacaine and Exparel®, an injectable liposomal bupivacaine
  • No effects on wound healing
  • Rat nerve block – comparable efficacy to Exparel®
  • No morbidity, mortality or toxicity signs, no gross pathological abnormalities; MTD > 100 mg/kg of Probudur bupivacaine (much greater than plain bupivacaine)
  • Rabbit: Probudur at a dose of 1.6 mg/kg was demonstrated to be as non-toxic to nerves as saline
  • Dog: No morbidity or mortality; EKG within normal limits up to 60 mg/kg; PK revealed low plasma levels of both Probudur and Exparel® with a similar Cmax

DOSE RESPONSE IN HEALTHY VOLUNTEERS

Duration of skin analgesia as assessed by pinprick after subcutaneous injection of 0.5% standard bupivacaine (BUP) or 0.5, 1.0, or 2.0% large multivesicular vesicle (LMVV) liposomal bupivacaine1

PIG: WOUND MODEL: PROBUDUR SUPERIOR TO BUPIVACAINE AND EXPAREL® AT 96 HOURS2

Probudur peak achieved around 6 hours with persistent analgesia noted at 96 hours- 24 hours longer than competitor claims

OPIOID SPARING BENEFITS

ENHANCED RECOVERY AFTER SUGERY (ERAS)

  • Rapidly becomingstandard of care in perioperative medicine
  • Earlier recovery ofbowels, bladder,pulmonary system, etc.

REDUCED OPIOID RELATED ADVERSE EVENTS (ORAEs)

  • Reduced length of stay
  • Less cognitive dysfunction by opioid sparing
  • Less nausea, vomiting

HEALTH ECONOMIC OUTCOME BENEFITS

  • Cost savings
  • Earlier ambulation
  • Earlier discharge
  • Improved medical outcomes
  • Improved patient satisfaction

CONCLUSION

  • Effective analgesia enhances recovery and reduces postoperative morbidity
  • Depot formulations of local anesthetics remain at the site of injection and release drug slowly over time
  • Results in prolonged analgesic effect with a reduction in plasma concentrations compared to standard anesthetics
  • Probudur demonstrated 96-hour activity, efficacy, tolerability and safety in multiple animal models
  • All ingredients are biocompatible, biodegradable and GRAS
  • A successful pre-IND meeting with FDA allows for a 505(b)(2) FDA regulatory approval pathway
  • Probudur is a promising ultra-long-acting depot local anesthetic for intraoperative use with the potential to spare opioids and minimize opioid related adverse effects
  1. Grant G, Barenholz Y. Anesthesiology 2004; 101:133-7
  2. Lipocure (data on file)

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